Project Summary (Overall) This renewal application aims to continue research on rare eosinophilic gastrointestinal diseases with a focus on eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), and eosinophilic colitis (EC) through the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). CEGIR will promote highly collaborative, multi-site, patient-centric, translational, and clinical research with the intent of addressing unmet clinical trial readiness needs. CEGIR comprises clinical centers in Ohio (coordinating center), Colorado, Arkansas, California, Illinois, Maryland, Massachusetts, Minnesota, New York, North Carolina, Pennsylvania, Tennessee, Texas, and Utah. The CEGIR sites have been carefully chosen on the basis of their pre-existing record of collaboration and success with each other before and during the first cycle of CEGIR; diverse expertise in relevant clinical specialties including Gastroenterology, Allergy, Immunology, Nutrition, and Pathology; the ability to integrate pediatric and adult patients into a common consortium; well-established record of excellence in clinical and translational research involving this patient population; and excellent mentorship experience and capacity to impact early stage trainees? career development. CEGIR sites have proven access to an adequate number of patients with EoE, EG, EGE, and EC, as evidenced from completion of several controlled clinical trials involving these patients. Proactive patient advocacy groups (PAGs), including the American Partnership for Eosinophilic Disorders and the Campaign Urging Research for Eosinophilic Disease, partner synergistically in the context of CEGIR. Though still in a relatively early stage, CEGIR is demonstrating success via its collaborative interactions between investigators (at all stages of career development including newly established promising faculty who represent the next generation of thought leaders), highly engaged PAGs, and partnering institutions and has emerged into the leading research group focused on rare EoE, EG, EGE, and EC. Current and proposed CEGIR initiatives are developing clinical trial readiness for this set of rare diseases, such as the establishment of deeply phenotyped and genotyped patients who are ready to participate in research and emerging tools that quantify clinical states, endoscopic abnormalities, tissue pathology, and patient well-being. In this renewal application, investigators plan to study an already developed observational cohort of patients, providing a valuable opportunity for longitudinal analyses. Data emerging from this cohort has already substantiated the association of type 2 allergic immunity (e.g. IL-13) in the pathogenesis of EG, leading to a proposal, described herein, to examine the impact of a promising new anti-type 2 immunity therapeutic (dupilumab, anti-IL-4Ra). CEGIR includes transformative Pilot-Feasibility and Career Enhancement Cores based on collaboration across and outside of the RDCRN and which will collectively test novel hypotheses, particularly focused on enhancing clinical trial readiness and attracting early stage investigators for careers in rare disease research.